ClinVar Miner

Submissions for variant NM_001163817.2(DHCR7):c.1A>G (p.Met1Val) (rs104886033)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169384 SCV000220774 likely pathogenic Smith-Lemli-Opitz syndrome 2014-10-07 criteria provided, single submitter literature only
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224026 SCV000280787 pathogenic not provided 2015-01-30 criteria provided, single submitter clinical testing
GeneDx RCV000224026 SCV000568697 likely pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing The c.1A>G variant in the DHCR7 gene has been reported previously in two unrelated individuals with mild Smith-Lemli-Optiz syndrome when in trans with a splice site variant (Scalco et al., 2005; Witsch-Baumgartner et al., 2005). As this variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. In addition, a report has shown that protein initiation at Met59 of the DHCR7 gene does gives rise to a functional protein (Scalco et al., 2005). The c.1A>G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.1A>G variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169384 SCV000697854 likely pathogenic Smith-Lemli-Opitz syndrome 2017-07-20 criteria provided, single submitter clinical testing Variant summary: The DHCR7 c.1A>G (p.Met1Val) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/121390 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). This variant has been reported in multiple compound heterozygous SLOS patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. The variant of interest affects the translational start sight, however, Scalco_2005 indicates that translational initiation at Methionine 59 produces a functional protein. Therefore, suggesting that this would help explain the mild phenotype observed in affected individuals. Taken together, this variant is classified as likely pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000169384 SCV000923648 pathogenic Smith-Lemli-Opitz syndrome 2019-01-01 criteria provided, single submitter clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000169384 SCV000999307 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Baylor Genetics RCV000169384 SCV001163344 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Invitae RCV000169384 SCV001236046 pathogenic Smith-Lemli-Opitz syndrome 2020-07-21 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the DHCR7 mRNA. The next in-frame methionine is located at codon 59. This variant is present in population databases (rs104886033, ExAC 0.009%). This variant has been observed in individuals affected with Smith-Lemli-Opitz syndrome (PMID: 15776424, 15952211, 16983147, 21990131). ClinVar contains an entry for this variant (Variation ID: 6794). Disruption of the initiator codon has been determined to be pathogenic (PMID: 12949967). This suggests that this variant is also likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001267308 SCV001445489 pathogenic Inborn genetic diseases 2020-05-27 criteria provided, single submitter clinical testing
OMIM RCV000169384 SCV000027392 pathogenic Smith-Lemli-Opitz syndrome 2005-07-30 no assertion criteria provided literature only
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000169384 SCV001469211 pathogenic Smith-Lemli-Opitz syndrome 2020-05-06 no assertion criteria provided clinical testing

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